Sox2 amplification was recently reported as a common event in squamous cell carcinomas (SCCs) occurring at different anatomic sites including the lung. The objective of the study was to determine morphologic and clinicopathologic characteristics of lung SCCs with respect to Sox2 protein expression and gene amplification. One hundred forty-seven surgically treated non-small cell lung carcinomas were analyzed for Sox2 gene amplification by using fluorescence in situ hybridization and protein expression using immunohistochemical analysis. SCC showed more frequent Sox2 protein expression (52/66; 79%) than adenocarcinomas (ADC) (14/76; 18%) (P < .0001). Similarly, Sox2 amplification was more frequent in SCCs (52/70; 72%) than in ADCs (6/77; 8%) (P < .0001). Sox2 protein expression was associated with better overall survival in SCC (66 vs 14 months; P =.048). SCC with basaloid differentiation and severe nuclear atypia exhibited more intense Sox2 protein expression than other tumors. Sox2 appears to be an important gene in lung squamous cell carcinogenesis that in particular drives the development of poorly differentiated tumors.